Advertisement

Immunotherapy of Myasthenia Gravis

  • C. Antozzi
  • F. Baggi
  • F. Andreetta
  • M. Milani
  • A. Annoni
  • P. Bernasconi
  • R. Mantegazza
  • F. Cornelio
Part of the Topics in Neuroscience book series (TOPNEURO)

Abstract

Myasthenia gravis (MG) is an acquired autoimmune disease of the neuromuscular junction mediated by antibodies against the nicotinic acetylcholine receptor (anti-AChR Ab). Anti-AChR Ab, by cross-linking AChR molecules and activating the complement cascade, cause destruction of junctional AChR and simplification of the post-synaptic membrane [1, 2]. The reduced number of functional AChR accounts for the impaired neuromuscular transmission, leading to the muscle weakness and fatigability typical of MG patients. For a review of the clinical features of MG, see [3].

Keywords

Acetylcholine Receptor Cell Epitope Recombinant Fragment Altered Peptide Ligand Myasthenic Crisis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Marx A, Wilisch A, Schultz A et al (1997) Pathogenesis of myasthenia gravis. Virchows Arch 430:355–364CrossRefGoogle Scholar
  2. 2.
    Lindstrom JM (2000) Acetylcholine receptors and myasthenia. Muscle Nerve 23:453–477PubMedCrossRefGoogle Scholar
  3. 3.
    Engel AG (1994) Aquired autoimmune myasthenia gravis. In: Engel AG, Franzini-Armstrong G (eds) Myology, vol 2. McGraw-Hill, New York, pp 1769–1797Google Scholar
  4. 4.
    Grob D, Arsura E, Brunner N, Namba T (1987) The course of myasthenia gravis and therapies affecting outcome. Ann NY Acad Sei 505:472–499CrossRefGoogle Scholar
  5. 5.
    Drachman D (1996) Immunotherapy in neuromuscular disorders: current and future strategies. Muscle Nerve 19:1239–1251PubMedCrossRefGoogle Scholar
  6. 6.
    Blalock A (1944) Thymectomy in the treatment of myasthenia gravis. Report of 20 cases. J Thorac Surg 13:316–339Google Scholar
  7. 7.
    Jaretzki A III (1997) Thymectomy for myasthenia gravis. Analysis of the controversies regarding technique and results. Neurology 48 (Suppl 5):S52–S63CrossRefGoogle Scholar
  8. 8.
    Scelsi R, Ferro MT, Scelsi L et al (1996) Detection and morphology of thymic remnants after video-assisted thoracoscopic extended thymectomy (VATET) in patients with myasthenia gravis. Int Surg 81:14–17PubMedGoogle Scholar
  9. 9.
    Mantegazza R, Confalonieri P, Antozzi C et al (1998) Video-assisted thoracoscopic extended thymectomy (VATET) in myasthenia gravis. Ann NY Acad Sei 841:749–752CrossRefGoogle Scholar
  10. 10.
    Gronseth GS, Barohn RJ (2000) Practice parameter: thymectomy for autoimmune myasthenia gravis (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 55:7–15PubMedCrossRefGoogle Scholar
  11. 11.
    Sghirlanzoni A, Peluchetti D, Mantegazza R et al (1984) Myasthenia gravis: prolonged treatment with steroids. Neurology 34:170–174PubMedCrossRefGoogle Scholar
  12. 12.
    Arsura E, Brunner NG, Namba T, Grob D (1985) High-dose intravenous methylpred-nisolone in myasthenia gravis. Arch Neurol 42:1149–1153PubMedCrossRefGoogle Scholar
  13. 13.
    Cornelio F, Antozzi C, Mantegazza R et al (1993) Immunosuppressive treatments. Their efficacy on myasthenia gravis patients’ outcome and on the natural course of the disease. Ann NY Acad Sei 681:594–602CrossRefGoogle Scholar
  14. 14.
    Mertens HG, Hertel H, Reuther P, Ricker K (1981) Effect of immunosuppressive drugs (Azathioprine). Ann NY Acad Sei 377:691–699CrossRefGoogle Scholar
  15. 15.
    Mantegazza R, Antozzi C, Peluchetti D et al (1988) Azathioprine as a single drug or in combination with steroids in the treatment of myasthenia gravis. J Neurol 235:449-453PubMedCrossRefGoogle Scholar
  16. 16.
    Hohlfeld R, Michels M, Heininger K et al (1988) Azathioprine toxicity during long-term immunosuppression of generalized myasthenia gravis. Neurology 38:258–261PubMedCrossRefGoogle Scholar
  17. 17.
    Gajdos P, Elkharrat D, Chevret A et al (1993) A randomized clinical trial comparing prednisone and azathioprine in myasthenia gravis. Results of the second interim analysis. J Neurol Neurosurg Psychiatry 56:1157–1163CrossRefGoogle Scholar
  18. 18.
    Palace J, Newsom-Davis J, Lecky B (1998) A randomized double-blind trial of prednisolone alone or with azathioprine in myasthenia gravis. Myasthenia Gravis Study Group. Neurology 50:1778–1783PubMedCrossRefGoogle Scholar
  19. 19.
    Hohlfeld R, Toyka KV, Besinger UA et al (1985) Myasthenia gravis: reactivation of clinical disease and of autoimmune factors after discontinuation of long-term azathio-prine. Ann Neurol 17:238–242PubMedCrossRefGoogle Scholar
  20. 20.
    Nyberg-Hansen N, Gjerstad L (1988) Myasthenia gravis treated with cyclosporin. Acta Neurol Scand 77:307–313Google Scholar
  21. 21.
    Goulon M, Elkharrat D, Gajdos P (1989) Treatment of severe myasthenia gravis with cyclosporin. A 12-month open trial. Presse Med 18:341–346PubMedGoogle Scholar
  22. 22.
    Tindall RS, RoUins JA, Phillips JT et al (1987) Preliminary results of a double-blind, randomized, placebo-controlled trial of cyclosporine in myasthenia gravis. N Engl J Med 316:719–724CrossRefGoogle Scholar
  23. 23.
    Perez MC, Buot WL, Mercado-Danguilan C et al (1981) Stable remissions in myasthenia gravis. Neurology 31:32–37PubMedCrossRefGoogle Scholar
  24. 24.
    Niakan E, Harati Y, Rolak LA (1986) Immunosuppressive drug therapy in myasthenia gravis. Arch Neurol 43: 155–156PubMedCrossRefGoogle Scholar
  25. 25.
    Pinching AJ, Peters DK, Newsom-Davis J (1976) Remission of myasthenia gravis following plasma exchange. Lancet ii: 1373–1376CrossRefGoogle Scholar
  26. 26.
    Antozzi C, Gemma M, Regi B et al (1991) A short plasma exchange protocol is effective in severe myasthenia gravis. J Neurol 238:103–107PubMedCrossRefGoogle Scholar
  27. 27.
    Antozzi C, Berta E, Gonfalonieri P et al (1994) Protein-A adsorption is effective in immunosuppression resistant myasthenia gravis. Lancet 343:124PubMedCrossRefGoogle Scholar
  28. 28.
    Berta E, Confalonieri P, Simoncini 0 et al (1994) Removal of antiacetylcholine receptor antibodies by protein A immunoadsorption in myasthenia gravis. Int J Artif Organs 17:455–460Google Scholar
  29. 29.
    Howard JF (1998) Intravenous immunoglobulins for the treatment of acquired myasthenia gravis. Neurology 51(Suppl 5):S30–S36PubMedCrossRefGoogle Scholar
  30. 30.
    Gajdos P, Chevret S, Clair B et al (1997) Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Myasthenia Gravis Clinical Study Group. Ann Neurol 41:789–796PubMedCrossRefGoogle Scholar
  31. 31.
    Qureshi AI, Choudhry MA, Akbar S et al (1999) Plasma exchange and intravenous immunoglobulin treatment in myasthenic crisis. Neurology 52:629–632PubMedCrossRefGoogle Scholar
  32. 32.
    Strieker RB, Kwiatkowska BJ, Habis JA, Kiprov DD (1993) Myasthenia gravis: response to plasmapheresis following failure of intravenous immunoglobulins. Arch Neurol 50:837–840CrossRefGoogle Scholar
  33. 33.
    Christadoss P, Poussin M, Deng C (2000) Animal models of myasthenia gravis. Clin Immunol 94:75–87.Google Scholar
  34. 34.
    Lindstrom JM (2000) Acetylcholine receptors and myasthenia. Muscle Nerve 23:453–477PubMedCrossRefGoogle Scholar
  35. 35.
    Tzartos S, Barkas T, Cung, T et al (1998) Anatomy of the antigenic structure of a large membrane antigen, the muscle type nicotinic acetylcholine receptor. Immunol Rev 163:89–120PubMedCrossRefGoogle Scholar
  36. 36.
    Drachman DB, Mcintosh KR, Yang B (1998) Factors that determine the severity of experimental myasthenia gravis. Ann NY Acad Sei 841:262–282CrossRefGoogle Scholar
  37. 37.
    Christadoss P, Lindstrom J, Melvold R, Talal N (1985) I-A subregion mutation prevents experimental autoimmune myasthenia gravis. Immunogenetics 21:33–38PubMedCrossRefGoogle Scholar
  38. 38.
    Kaul R, Shenoy M, Goluzko E, Christadoss P (1994) Major histocompatibility complex class II gene disruption prevents experimental autoimmune myasthenia gravis. J Immunol 152:3152–3157Google Scholar
  39. 39.
    Shenoy M, Goluzsko E, Christadoss P (1994) The pathogenic role of acetylcholine receptor a chain epitope within a 146-162 in the development of experimental autoimmune myasthenia gravis in C57BL6 mice. Clin Immunol Immunopathol 73:338–343PubMedCrossRefGoogle Scholar
  40. 40.
    Bellone M, Ostlie N, Lei S, Conti-Tronconi BM (1991) Experimental myasthenia gravis in congenic mice: sequence mapping and H-2 restriction of T helper epitopes on the a-subunits of Torpedo caUfornica and murine acetylcholine receptor. Eur J Immunol 21:2303–2310PubMedCrossRefGoogle Scholar
  41. 41.
    Fujii Y, Lindstrom J (1998) Specificity of the T cell immune response to acetylcholine receptor in experimental autoimmune myasthenia gravis: response to subunits and synthetic peptides. J Immunol 140:1830–1837Google Scholar
  42. 42.
    Drachman DB (1996) Immunotherapy in neuromuscular disorders: current and future strategies. Muscle Nerve 19:1239–1251PubMedCrossRefGoogle Scholar
  43. 43.
    Killen J, Lindstrom J (1984) Specific killing of lymphocytes which cause EAMG by ricin acetylcholine receptor conjugates. J Immunol 133:2549–2553PubMedGoogle Scholar
  44. 44.
    Mcintosh KR, Linsley PS, Bacha PA, Drachman DB (1998) Immunotherapy of experimental myasthenia gravis: selective effects of CTLA4Ig and synergistic combination of IL-2-diphtheria toxin fusion protein. J Neuroimmunol 87:136–146PubMedCrossRefGoogle Scholar
  45. 45.
    Wu J-M, Wu B, Guarnieri F et al (2000) Targeting antigen specific T cells by genetically engineered antigen presenting cells. A strategy for specific immunotherapy of autoimmune disease. J Neuroimmunol 106:145–153PubMedCrossRefGoogle Scholar
  46. 46.
    Weiner HL (1997). Oral tolerance: immune mechanisms and treatment of autoimmune diseases. Immunol Today 18:335–343PubMedCrossRefGoogle Scholar
  47. 47.
    Wang ZY, Qiao J, Link H (1993) Suppression of experimental autoimmune myasthenia gravis by oral administration of acetylcholine receptor. J Neuroimmunol 44: 209–214PubMedCrossRefGoogle Scholar
  48. 48.
    Okumura S, Mcintosh K, Drachman DB (1994) Oral administration of acetylcholine receptor: effects on experimental autoimmune myasthenia gravis. Ann Neurol 36:704–713PubMedCrossRefGoogle Scholar
  49. 49.
    Ma CG, Zhang GX, Xiao BG et al (1995) Suppression of experimental autoimmune myasthenia gravis by nasal administration of acetylcholine receptor. J Neuroimmunol 58:51–60PubMedCrossRefGoogle Scholar
  50. 50.
    Drachman DB, Okumura S, Adams RN, Mcintosh K (1996) Oral tolerance in myasthenia gravis. Ann N Y Acad Sei 778:258–272CrossRefGoogle Scholar
  51. 51.
    Barehan D, Souroujon M, Im S-H et al (1999) Antigen specific modulation of experimental myasthenia gravis: nasal tolerization with recombinant fragments of the human acetylcholine receptor a subunit. Proc Natl Acad Sei USA 96:8086–8091CrossRefGoogle Scholar
  52. 52.
    Im S-H, Barehan D, Fuchs S, Souroujon MC (1999) Suppression of ongoing experimental myasthenia by oral treatment with an acetylcholine receptor recombinant fragment. J Clin Invest 104:1723–1730PubMedCrossRefGoogle Scholar
  53. 53.
    Im S-H, Barehan D, Souroujon MC, Fuchs S (2000) Role of tolerogen conformation in induction of oral tolerance in experimental autoimmune myasthenia gravis. J Immunol 165:3599–3605Google Scholar
  54. 54.
    Bartfeld D, Fuchs S (1973) Specific immunosuppression of experimental myasthenia gravis by denatured acetylcholine receptor. Proc Natl Acad Sei USA 75:4006–4010CrossRefGoogle Scholar
  55. 55.
    Wu B, Deng C, Goluszko E, Christadoss P (1997) Tolerance to a dominant T cell epitope in the acetylcholine receptor molecule induces epitope spread and suppresses murine myasthenia gravis. J Immunol 159:3016–3023PubMedGoogle Scholar
  56. 56.
    Karachunski PI, Ostlie NS, Okita DK et al (1999) Subcutaneous administration of T-epitope sequences of the acetylcholine receptor prevents experimental myasthenia gravis. J Neuroimmunol 93:108–121PubMedCrossRefGoogle Scholar
  57. 57.
    Karachunski PI, Ostlie NS, Okita DK, Conti-Fine BM (1997) Prevention of experimental myasthenia gravis by nasal administration of synthetic acetylcholine receptor T-epitope sequences. J Clin Invest 100:3027–3035PubMedCrossRefGoogle Scholar
  58. 58.
    Baggi F, Andreetta F, Caspani E et al (1999) Oral administration of an immunodominant T-cell epitope downregulates Thl/Yh2 cytokines and preventes experimental myasthenia. J Clin Invest 104:1287–1295PubMedCrossRefGoogle Scholar
  59. 59.
    Katz-Levy Y, Kirshner SL, Sela M, Mozes E (1993) Inhibition of T-cell reactivity to myasthenogenic epitopes of the human acetylcholine receptor by synthetic analogs. Proc Natl Acad Sei USA 90:7000–7004CrossRefGoogle Scholar
  60. 60.
    Katz-Levy Y, Paas-Rozner M, Kirshner S et al (1997) A peptide composed of tandem analogs of two myasthenogenic T cell epitopes interferes with specific autoimmune responses. Proc Natl Acad Sei USA 94:3200–3205CrossRefGoogle Scholar
  61. 61.
    Katz-Levy Y, Dayan M, Wirguin I et al (1998) Single amino acid analogs of a myasthenogenic peptide modulate specific T cell responses and prevent the induction of experimental myasthenia gravis. J Neuroimmunol 85:78–86PubMedCrossRefGoogle Scholar
  62. 62.
    Faber-Elmann A, Paas-Rozner M, Sela M, Mozes E (1998) Altered peptide ligands act as partial agonists by inhibiting phospholipase C activity induced by myasthenogenic T cell epitopes. Proc Natl Acad Sei USA 95:14320–14325CrossRefGoogle Scholar
  63. 63.
    Paas-Rozner M, Dayan M, Paas Y et al (2000) Oral administration of a dual analog of two myasthenogenic T cell epitopes down-regulates experimental autoimmune myasthenia gravis in mice. Proc Natl Acad Sei USA 97:2168–2173CrossRefGoogle Scholar
  64. 64.
    Spack EG, McCutcheon M, Corbelletta N et al (1995) Induction of tolerance in experimental autoimmune myasthenia gravis with solubilized MHC classll: acetylcholine receptor peptide complexes. J Autoimmun 8:787–807PubMedCrossRefGoogle Scholar
  65. 65.
    Araga S, LeBoeuf RD, Blalock JE (1993) Prevention of experimental autoimmune myasthenia gravis by manipulation of the immune network with a complementary peptide for the acetylcholine receptor. Proc Natl Acad Sei USA 90:8747–8751CrossRefGoogle Scholar
  66. 66.
    Protti MP, Manfredi AA, Horton RM et al (1993) Myasthenia gravis: recognition of a human autoantigen at the molecular level. Immunol Today 14:363–368PubMedCrossRefGoogle Scholar
  67. 67.
    Hawke S, Matsuo H, NicoUe M et al (1996) Autoimmune T cells in myasthenia gravis: heterogeneity and potential for specific immunotargeting. Immunol Today 17:307–311PubMedCrossRefGoogle Scholar
  68. 68.
    Wang ZY, Okita DK, Howard J, Conti-Fine BM (1997) Thl epitope repertoire on the alpha subunit of human muscle acetylcholine receptor in myasthenia gravis. Neurology 48:1643–1653PubMedCrossRefGoogle Scholar
  69. 69.
    Hill M, Beeson D, Moss P et al (1999) Early-onset myasthenia gravis: a recurring T-cell epitope in the adult-specific acetylcholine receptor epsilon subunit presented by the susceptibility allele HLA-DR52a. Ann Neurol 45:224–231PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2002

Authors and Affiliations

  • C. Antozzi
    • 1
  • F. Baggi
    • 1
  • F. Andreetta
    • 1
  • M. Milani
    • 1
  • A. Annoni
    • 1
  • P. Bernasconi
    • 1
  • R. Mantegazza
    • 1
  • F. Cornelio
    • 2
  1. 1.Myopathology and Immunology Unit, Department of Neuromuscular DiseasesNational Neurological Institute “Carlo Besta”MilanItaly
  2. 2.Department of Neuromuscular DiseasesNational Neurological Institute “Carlo Besta”MilanItaly

Personalised recommendations